Enzymes are protein molecules which serve to accelerate the chemical reactions of living cells (often by several orders of magnitude). Without enzymes, most biochemical reactions would be too slow to even carry out life processes. Enzymes display great specificity and are not permanently modified by their participation in reactions. Since they are not changed during the reactions, enzymes can be cost effectively used as catalysts for a desired chemical transformation.
Ketoreductases are a specific class of enzymes that catalyze the direct reduction of prochiral ketones to chiral alcohols. Enantiomerically pure chiral alcohols are key intermediates in a number of pharmaceutical compounds that possess a wide range of biological activities. Currently there is considerable effort underway to develop efficient catalytic methods for their preparation utilizing biocatalysts. Ketoreductases have emerged as promising biocatalysts for chiral alcohol production with approximately 30% of the reported industrial biotransformation using ketoreductases. Straathof, A. J.; Panke, S.; Schmid, A. Curr. Opin. Biotechnol. 2002, 13, 548-556.
For example, (−)-Bchlorodiisopinocampheylborane (i.e., (−)-DIP-Cl or (−)-Ipc2BCl) was originally for the large scale manufacture of the allergy medication montelukast sodium (SINGULAIR). (−)-DIP-Cl was replaced with a ketoreductase which ultimately has lead to an enzymatic process that reduces waste, improves yield and safety, and eliminates the need for (−)-DIP-Cl. Liang, J.; Lalonde, J.; Borup, B.; et al. Org. Process Res. Dev. 2010, 14, 193-198.
Though advances in producing chiral alcohols using ketoreductases have been highly regarded, there still exits some drawbacks to the enzymatic process. Currently enzymatic processes can only be run in aqueous solvent systems, as the ketoreductases are not stable in 100% organic solvents or near 100% organic solvents. Additionally, during product alcohol isolation, the ketoreductase catalyst is deactivated and discarded resulting in the inability to reuse the catalyst.
Thus, though attempts have been made to immobilize ketoreductases none have been successful in overcoming their lack of stability, more specifically their lack of stability in organic solvents.